A concise synthesis of natural benzofuran neolignans and analogues

Article abstract of DOI:10.1055/s-0029-1218826

The first total synthesis of four naturally occurring benzofuran neolignans and two analogues was achieved in four steps in 44-51% overall yield. Key steps involved a two-step construction of benzofuran nucleus and a Suzuki coupling. This synthesis has been proven straightforward and efficient, and more related analogues can be prepared for structure-activity relationship explorations. Georg Thieme Verlag Stuttgart New York.

Full text of DOI:10.1055/s-0029-1218826

PAPER
2547
A Concise Synthesis of Natural Benzofuran Neolignans and Analogues
Synthesis of
N
atur
i
a
l
Benz
n
ofuran Neol
-
ignans Fang Duan,* Gang Shen, Zhan-Bin Zhang
Department of Chemistry, Beijing Normal University, Beijing 100875, P. R. of China
Fax +86(10)58802075; E-mail: xinfangduan@vip.163.com
Received 23 March 2010; revised 2 April 2010
the corresponding o-vinylphenol 5, which can be formed
through a selective McMurry cross-coupling of readily
available 5-bromosalicylaldehyde or 5-bromo-3-methoxy-
salicylaldehyde with an aromatic aldehyde 7. This effi-
Abstract: The first total synthesis of four naturally occurring ben-
zofuran neolignans and two analogues was achieved in four steps in
44–51% overall yield. Key steps involved a two-step construction
of benzofuran nucleus and a Suzuki coupling. This synthesis has
been proven straightforward and efficient, and more related ana- cient route should allow for the synthesis of gram
logues can be prepared for structure-activity relationship explora-
tions.
quantities of the neolignans to facilitate the preparation of
their analogues as well as corresponding biological activ-
Key words: benzofuran, neolignan, McMurry reaction, Suzuki
coupling
ity evaluation.
R3
O
Lignans and neolignans are richly present in nature and
exhibit a broad range of biological activities.1 Benzofuran
lignans and neolignans are characteristic members of this
family. Various benzofuran neolignans such as ailan-
thoidol,2 XH-14,3 obovaten,4 egonol,5 and homoegonol6
have been isolated and attracted wide attention for their
significant pharmacological potentials. Benzofuran neo-
lignans 1a–d (Figure 1) were isolated from Krameria spe-
cies.7 Among them, compound 1a exhibited valuable
antifungal activity8 and potential for use as antioxidants
and radical scavengers.9 Although preparation for neolig-
nans such as ailanthoidol,10 XH-14,11 obovaten,1 and
egonol12 have been reported, total synthesis of neolignans
1a–d has not been documented. To this end we continued
our efforts to develop a reliable and efficient synthetic
route to these benzofuran neolignans and analogues, and
thus to explore the corresponding biological activities.
R2
R1
1
Br
R3
+
B(OH)2
O
R2
R1
3
4
Br
R3
OH
R2
R1
5
Br
OHC
R3
CHO
OH
+
R2
R1
R3
7
6
O
R2
R1
R1
Scheme 1 Retrosynthetic analysis of neolignans 1
R2
R3
In Scheme 2, the boronic acid 3 required for Suzuki cou-
plings was prepared and then converted into 2,4,6-tri(1-
propenyl)cyclotriboroxane–pyridine complex 3a accord-
ing to the reported procedure.13 The ratio of pyridine to
cyclotriboroxane in the complex 3a was about 1:1.3 as
1a
1b OMe
1c
1d OMe
H
OH
OH
H
OH
OH
OH
OH
H
H
Figure 1 Naturally occurring benzofuran neolignans 1
1
confirmed by its H NMR spectrum. Following Suzuki
As outlined in Scheme 1, our retrosynthetic analysis of
these neolignans 1a–d envisaged a convergent Suzuki
coupling between (E)-prop-1-enylboronic acid (3) and 5-
bromobenzofurans 4. The key intermediate 5-bromoben-
zofuran 4 could be obtained via oxidative cyclization from
coupling of 4 with 3a, compounds 2 (Scheme 3) were ob-
tained as a mixture of E/Z-isomers based on their 1H NMR
and 13C NMR spectra. Debenzylation of 2 with TiCl4 gave
the final products 1 as single E-isomers in high yields.
This indicated that a mixture of trans- and cis-1-bro-
moprop-1-ene can be used instead of more expensive (E)-
1-bromoprop-1-ene.
SYNTHESIS 2010, No. 15, pp 2547–2552
x
x.
x
x
.
2
0
1
0
Advanced online publication: 17.06.2010
DOI: 10.1055/s-0029-1218826; Art ID: Z07510SS
© Georg Thieme Verlag Stuttgart · New York

2548
X.-F. Duan et al.
PAPER
were prepared via the selective McMurry cross-
couplings14 using readily available 5-bromosalicylalde-
hyde (6a) or 5-bromo-3-methoxysalicylaldehyde (6b)
with aromatic aldehydes 7a–c in 65–75% isolated yields,
1. Mg, THF
2. (i-PrO)3B
3. aq HCl
B(OH)2
Br
3
15
and oxidative cyclization of 5a–e using I2/K2CO3 fur-
O
B
nished benzofurans in high yields (>90%). The natural
products neolignans 1a–d were obtained in 44–51% over-
all yield by incorporating the 1-propenyl building block
into the bromobenzofurans 4a–e via a sequential reaction
of Suzuki couplings using 3a, and debenzylation of 2a–e.
B
Py, Et2O
O
B
O
N
3a
It should be noted that our synthetic strategy can be readi-
ly applied to the synthesis of neolignan analogues. For in-
stance, (E)-2-(4-hydroxy-3-methoxyphenyl)-7-methoxy-
5-(prop-1-enyl)benzofuran (1e) was also facilely prepared
in a similar manner (Scheme 3). Another analogue, 2-(4-
hydroxy-3-methoxyphenyl)-7-methoxy-5-propylbenzo-
furan (1f), which was once synthesized by Scammells16 in
Scheme 2 Synthesis of 2,4,6-tri[(E/Z)-1-propenyl]cyclotriborox-
ane-pyridine complex 3a
As shown in Scheme 3, the key intermediate bromoben-
zofurans 4a–e were prepared through a two-step protocol
with 62–71% overall yield: first, o-vinylphenols 5a–e
R4
R3
Br
R4
R3
Br
CHO
OH
OHC
R2
K2CO3, I2, THF
TiCl4, Mn, THF
R2
+
OH
R1
R1
R1
H
R2
R3
R4
yield
6a: R1 = H
7a: R2 = R3 = OBn, R4 = H
7b: R2 = R4 = H, R3 = OBn
7c: R2 = H, R3 = OBn, R4 = OMe
5a
H
H
OBn OBn
65%
74%
6b: R1 = OMe
5b OMe OBn OBn
5c
5d OMe
5e
H
H
H
H
H
H
OBn
OBn
69%
72%
OMe
OBn OMe 75%
R4
R4
Br
3a
TiCl4
R3
R3
1
O
O
CH2Cl2
R2
Pd(PPh3)4
R1
R2
R1
4a: 96%; 4b: 92%;
4c: 92%; 4d: 95%;
4e: 94%
2a: 78%; 2b: 76%;
2c: 76%; 2d: 74%;
2e: 75%
1a: 95%; 1b: 98%;
1c: 92%; 1d: 92%;
1e: 91%
OMe
OH
OMe
OBn
Pd/C, H2
O
O
OMe
OMe
96%
2e
1f
OH
OH
OH
O
O
O
HO
HO
OMe
1a, total yield: 46%
1b, total yield: 51%
1c, total yield: 44%
OMe
OMe
OH
OH
OH
O
O
O
OMe
OMe
OMe
1d, total yield: 47%
1e, total yield: 48%
1f, total yield: 51%
Scheme 3 Total synthesis of natural neolignans 1a–d and two analogues 1e,f
Synthesis 2010, No. 15, 2547–2552 © Thieme Stuttgart · New York

PAPER
Synthesis of Natural Benzofuran Neolignans
2549
2-(2,4-Dibenzyloxystyryl)-4-bromo-6-methoxyphenol (5b)
White solid; mp 114–115 °C.
IR (KBr): 3410, 1599, 1505, 1426, 1279 cm–1.
24% overall yield and evaluated as adenosine antagonist,
was synthesized in a total yield of 51% starting from 6a
and 7c.
1H NMR (400 MHz, CDCl3): d = 7.55 (d, J = 9.3 Hz, 1 H), 7.47–
7.48 (m, 1 H), 7.44–7.45 (m, 2 H), 7.29–7.42 (m, 10 H), 6.84 (m, 1
H), 6.59–6.61 (m, 2 H), 5.78 (s, 1 H), 5.12 (s, 2 H), 5.05 (s, 2 H),
3.89 (s, 3 H).
13C NMR (100 MHz, CDCl3): d = 159.7, 157.2, 147.2, 142.2, 136.9,
136.8, 128.61, 128.59, 127.9, 127.5, 127.2, 126.3, 125.0, 121.1,
120.3, 119.9, 112.1, 111.6, 106.6, 100.96, 70.5, 70.2, 56.3.
In summary, we have achieved an efficient total synthesis
of naturally occurring neolignans 1a–d and two analogues
1e,f from readily available aldehydes in four steps in an
overall yield of 44–51%. This has featured a very effec-
tive approach to construct the neolignan skeleton employ-
ing a two-step synthesis of bromobenzofuran and a
sequential Suzuki coupling. Because the reagents are
readily available and the operations are straightforward,
our synthesis proves to be more convenient and effective
with higher yields compared with previously reported
methods.
MS (EI): m/z (%) = 517 (23, [81Br, M+]), 425 (23), 346 (20), 91
(100).
Anal. Calcd for C29H25BrO4: C, 67.32; H, 4.87. Found: C, 67.58; H,
5.14.
2-(4-Benzyloxystyryl)-4-bromophenol (5c)
White solid; mp 150–152 °C.
IR (KBr): 3444, 1606, 1511, 1247 cm–1.
All glassware was oven-dried (120 °C) and cooled under a stream
of argon gas. The reagents and solvents used for the pinacol-type
couplings were freshly distilled or dehydrated before use. All other
starting materials were obtained from commercial suppliers and
were used without further purification. Petroleum ether (PE) used
refers to the fraction boiling in the range 60–90 °C. Analytical TLC
was conducted using QDHY GF254 plates. Column chromatogra-
phy was performed using QDYD silica gel (200–300 mesh). Melt-
ing points were recorded on a TECH X-4 microscopic instrument
and are uncorrected. IR spectra were obtained using a Vaatar 360
FT-IR spectrophotometer. 1H and 13C NMR spectra were recorded
at 400 MHz and 100 MHz, respectively, using a Bruker Avance 400
spectrometer and TMS as the internal standard. Mass spectra were
recorded on a Traces MS spectrometer. Elemental analyses were
obtained using an Elementar Vario EL instrument.
1H NMR (400 MHz, CDCl3): d = 7.54 (d, J = 2.4 Hz, 1 H), 7.25–
7.40 (m, 7 H), 7.13 (dd, J = 2.4, 8.5 Hz, 1 H), 7.00 (dd, J = 6.4, 3.6
Hz, 2 H), 6.90 (d, J = 8.7 Hz, 2 H), 6.61 (d, J = 8.5 Hz, 1 H), 5.02
(s, 2 H), 4.86 (s, 1 H).
13C NMR (100 MHz, CDCl3): d = 158.8, 151.8, 136.8, 131.7, 130.9,
130.7, 130.1, 129.4, 128.6, 128.1, 128.0, 127.5, 127.2, 119.4, 117.5,
115.1, 113.4.
MS (EI): m/z (%) = 382 (85, [81Br, M+]), 291 (85), 181 (100), 151
(90).
Anal. Calcd for C21H17BrO2: C, 66.16; H, 4.49. Found: C, 66.38; H
4.78.
2-(4-Benzyloxystyryl)-4-bromo-6-methoxyphenol (5d)
White solid; mp 123–125 °C.
IR (KBr): 3504, 1600, 1510, 1477, 1242 cm–1.
1H NMR (500 MHz, CDCl3): d = 7.57 (d, J = 8.5 Hz, 2 H), 7.51 (d,
J = 7.5 Hz, 2 H), 7.24–7.43 (m, 6 H), 7.06 (d, J = 9.0 Hz, 2 H), 6.99
(d, J = 1.5 Hz, 1 H), 5.17 (s, 2 H), 3.91 (s, 3 H), 3.00 (s, 1 H).
13C NMR (100 MHz, CDCl3): d = 158.8, 148.5, 143.2, 137.4, 130.6
129.4, 128.4, 127.83, 127.78, 127.6, 126.0, 120.4, 119.7, 115.1,
112.8, 110.8, 69.6, 55.9.
2-(2,4-Dibenzyloxystyryl)-4-bromophenol (5a); Typical Proce-
dure
Under argon, a four-necked flask equipped with a magnetic stirrer
was charged with Mn powder (1.4 g, 24 mmol) and THF (80 mL).
The mixture was cooled to –5 to 0 °C, and TiCl4 (1.3 mL, 12 mmol)
was added by a syringe slowly by keeping the temperature under 0
°C. The suspension was warmed to r.t. and stirred for 0.5 h, then
heated at reflux for 2.5 h. The mixture was again cooled to –5 to 0
°C, and a solution of 5-bromosalicylaldehyde (6a; 0.48 g, 2.4
mmol) and 2,4-dibenzyloxybenzaldehyde (7a; 0. 89 g, 2.8 mmol) in
THF (30 mL) was added slowly. After the addition, the reaction
mixture was heated at reflux until the carbonyl compounds were
consumed (monitored by TLC). The reaction was quenched with
10% aq NaHCO3 (25 mL) and extracted with CH2Cl2 (3 × 20 mL).
The combined organic layers were dried (Na2SO4) and concentrat-
ed. The crude material was purified by flash chromatography over
silica gel (PE–EtOAc, 5:1) to give the title product 5a as a white sol-
id; mp 133–134 °C.
MS (EI): m/z (%) = 410 (40, [81Br, M+]), 319 (65), 197 (80), 91
(100).
Anal. Calcd for C22H19BrO3: C, 64.25; H, 4.66. Found: C, 64.53; H,
4.94.
2-(4-Benzyloxy-3-methoxystyryl)-4-bromo-6-methoxyphenol
(5e)
White solid; mp 138–139 °C.
IR (KBr): 3419, 1595, 1513, 1462, 1266 cm–1.
1H NMR (400 MHz, CDCl3): d = 7.44 (d, J = 7.2 Hz, 2 H), 7.35–
7.39 (m, 2 H), 7.30–7.32 (m, 2 H), 7.17–7.21 (m, 1 H), 7.04–7.10
(m, 2 H), 6.99–7.01 (m, 1 H), 6.85–6.87 (m, 2 H), 5.85 (s, 1 H), 5.18
(s, 2 H), 3.95 (s, 3 H), 3.90 (s, 3 H).
13C NMR (100 MHz, CDCl3): d = 149.8, 148.2, 147.3, 142.3, 137.1,
131.0, 130.2, 128.6, 127.8, 127.2, 125.4, 121.1, 120.0, 119.8,
113.96, 112.3, 111.7, 109.5, 71.0, 56.4, 56.0.
IR (KBr): 3341, 1608, 1505, 1180 cm–1.
1H NMR (400 MHz, CDCl3): d = 7.57 (d, J = 2.4 Hz, 1 H), 7.32–
7.50 (m, 12 H), 7.19 (d, J = 2.4 Hz, 1 H), 7.15–7.17 (m, 1 H), 6.68
(d, J = 7.3 Hz, 1 H), 6.59–6.62 (m, 2 H), 5.11 (s, 2 H), 5.06 (s, 2 H),
4.86 (s, 1 H).
13C NMR (100 MHz, CDCl3): d = 159.9, 157.4, 151.9, 136.8, 136.7,
130.5, 129.5, 128.69, 128.65, 128.2 128.1, 128.07, 127.8, 127.5,
127.3, 126.8, 120.0, 119.8, 117.5, 113.3, 106.6, 101.0, 70.6, 70.2.
MS (EI): m/z (%) = 486 (15, [81Br, M+]), 395 (15), 181 (20), 91
(100).
MS (EI): m/z (%) = 440 (20, [81Br, M+]), 349 (100), 241 (25), 96
(100).
Anal. Calcd for C28H23BrO3: C, 69.00; H, 4.76. Found: C, 68.98; H,
4.86.
Anal. Calcd for C23H21BrO4: C, 62.60; H, 4.80. Found: C, 62.38; H,
4.52.
Synthesis 2010, No. 15, 2547–2552 © Thieme Stuttgart · New York

2550
X.-F. Duan et al.
PAPER
2-(2,4-Dibenzyloxyphenyl)-5-bromobenzofuran (4a); Typical
Procedure
1H NMR (500 MHz, CDCl3): d = 7.83 (d, J = 9.0 Hz, 2 H), 7.36–
7.49 (m, 5 H), 7.31 (d, J = 14.5 Hz, 1 H), 7.07 (d, J = 10 Hz, 2 H),
6.91 (d, J = 1.5 Hz, 1 H), 6.83 (s, 1 H), 5.15 (s, 2 H), 4.05 (s, 3 H).
13C NMR (125 MHz, CDCl3): d = 159.5, 157.2, 145.5, 142.8, 136.6,
132.4, 128.7, 128.1, 127.5, 126.7, 122.9, 115.9, 115.7, 115.2, 112.8,
109.8, 99.4, 70.1, 56.4.
To a solution of o-vinylphenol 5a (4.86 g, 10 mmol) in THF (100
mL) was added anhyd K2CO3 (7.7 g, 55.5 mmol) and the mixture
was stirred for 10 min. I2 (14.1 g, 55.5 mmol) was added, and the
mixture was stirred at r.t. until 5a was consumed. The mixture was
poured into sat. aq NaHCO3 (150 mL) and treated with sat. aq
NaHSO3 (50 mL) to remove the unreacted I2. The mixture was ex-
tracted with EtOAc (3 × 50 mL), the combined organic layers were
dried (Na2SO4) and concentrated. The crude material was purified
by flash chromatography over silica gel (PE–EtOAc, 5:1) to give
the title product 4a as a white solid; mp 151–153 °C.
MS (EI): m/z (%) = 408 (50, [81Br, M+]), 318 (45), 240 (100).
Anal. Calcd for C22H17BrO3: C, 64.56; H, 4.19. Found: C, 64.50; H,
3.83.
2-(4-Benzyloxy-3-methoxyphenyl)-5-bromo-7-methoxybenzo-
furan (4e)
White solid; mp 154–155.6 °C.
IR (KBr): 1613, 1513, 1476, 1208 cm–1.
1H NMR (400 MHz, CDCl3): d = 7.32–7.47 (m, 7 H), 7.30 (d,
J = 1.7 Hz, 2 H), 6.93–6.95 (m, 1 H), 6.90 (d, J = 1.7 Hz, 1 H), 6.82
(s, 1 H), 5.22 (s, 2 H), 4.03 (s, 3 H), 4.00 (s, 3 H).
13C NMR (100 MHz, CDCl3): d = 157.2, 149.8, 149.0, 145.4, 142.8,
136.8, 132.3, 128.6, 128.0, 127.3, 123.3, 118.2, 115.9, 115.7, 113.9,
109.8, 108.7, 99.8, 71.0, 56.3, 56.2.
IR (KBr): 1609, 1499, 1445, 1297 cm–1.
1H NMR (400 MHz, CDCl3): d = 7.98 (d, J = 9.3 Hz, 1 H), 7.60 (s,
1 H), 7.98 (d, J = 9.3 Hz, 1 H), 7.60 (d, J = 1.5 Hz, 1 H), 7.50 (d,
J = 1.6 Hz, 1 H), 7.27–7.48 (m, 10 H), 7.09 (s, 1 H), 6.71 (dd,
J = 2.1, 7 Hz, 1 H), 5.20 (s, 2 H), 5.11 (s, 2 H).
13C NMR (100 MHz, CDCl3): d = 160.3, 156.98, 153.7, 152.4,
136.5, 136.2, 128.8, 128.7, 128.3, 128.2, 127.7, 127.6, 126.3, 123.3,
115.5, 112.7, 111.98, 106.3, 103.9, 100.8, 70.7, 70.3.
MS (EI): m/z (%) = 484 (45, [81Br, M+]), 393 (15), 181 (35), 91
(100).
MS (EI): m/z (%) = 438 (15, [81Br, M+]), 346 (60), 240 (45), 91
(100).
Anal. Calcd for C28H21BrO3: C, 69.29; H, 4.36. Found: C, 69.05; H,
4.10.
Anal. Calcd for C23H19BrO2: C, 62.88; H, 4.36. Found: C, 63.10; H,
4.59.
2-(2,4-Dibenzyloxyphenyl)-5-bromo-7-methoxybenzofuran
(4b)
2,4,6-Tri[(E/Z)-1-propenyl]cyclotriboroxane-Pyridine Com-
plex 3a13
White solid; mp 123–125 °C.
IR (KBr): 1607, 1505, 1473, 1288 cm–1.
Triisopropyl borate (18.5 mL, 89.2 mmol) was added to THF (75
mL) in a flame-dried, four-necked flask kept under argon. The flask
was cooled to -78 °C in a dry ice/acetone bath, and prop-1-enylmag-
nesium bromide (freshly prepared and titrated according to the stan-
dard procedure,17 1.0 M in THF, 50 mL, 50 mmol) was added
dropwise over about 30 min to the borate solution. After the addi-
tion of the Grignard reagent, the reaction was allowed to stir for 1 h
at –78 °C. The reaction was quenched by adding 30% aq HCl (30
mL). After stirring for 30 min, the solution was warmed to r.t. and
extracted with Et2O (3 × 30 mL). The combined organic layers were
dried (Na2SO4) and concentrated to about 25 mL. Pyridine (10 mL)
was added to the solution and the resulting mixture was stirred at r.t.
for 5 h. The solvents were evaporated to give a pale yellow oil. Dis-
tillation under reduced pressure (85–90 °C/0.1 Torr) gave the prod-
uct as an oil, which solidified when stored in a refrigerator; yield:
3.3 g (70%).
1H NMR (400 MHz, CDCl3): d = 7.95 (dd, J = 1.3, 7.7 Hz, 1 H),
7.27–7.42 (m, 10 H), 7.15 (d, J = 1.7 Hz, 1 H), 6.99 (s, 2 H), 6.78
(d, J = 1.7 Hz, 1 H), 6.60–6.63 (m, 1 H), 5.11 (s, 2 H), 5.01 (s, 2 H),
3.94 (s, 3 H).
13C NMR (100 MHz, CDCl3): d = 160.3, 156.9, 153.6, 145.3, 141.8,
136.6, 136.3, 132.9, 128.7, 128.6, 128.3, 128.4, 128.3, 128.1, 127.7,
127.6, 115.9, 115.4, 112.6, 109.8, 106.3, 104.1, 100.7, 70.7, 70.3,
56.4.
MS (EI): m/z (%) = 514 (25) [81Br, M+], 425 (20), 344 (20), 91
(100).
Anal. Calcd for C29H23BrO4: C, 67.58; H, 4.50. Found: C, 67.50; H,
4.78.
2-(4-Benzyloxyphenyl)-5-bromobenzofuran (4c)
White solid; mp 197–199 °C.
IR (KBr): 1607, 1579, 1504, 1441, 1247 cm–1.
1H NMR (400 MHz, CDCl3): d = 8.75 (d, J = 5.6 Hz, 2 H), 7.95 (t,
J = 7.6 Hz, 1 H), 7.54–7.55 (m, 2 H), 6.41–6.62 (m, 4 H), 5.50 (d,
J = 17.3 Hz, 2 H), 5.39 (d, J = 13.6 Hz, 2 H), 1.77–1.99 (m, 12 H).
1H NMR (500 MHz, CDCl3): d = 7.82 (d, J = 8.6 Hz, 2 H), 7.69 (s,
1 H), 7.37–7.49 (m, 7 H), 7.07–7.09 (d, J = 9.0 Hz, 2 H), 6.85 (s, 1
H), 5.16 (s, 2 H).
13C NMR (125 MHz, CDCl3): d = 159.5, 157.3, 153.5, 136.6, 131.5,
128.7, 128.2, 127.5, 127.5, 126.63, 126.56, 123.2, 123.0, 115.9,
115.3, 99.1, 70.1.
MS (EI): m/z (%) = 204 (3, [M+]), 162 (8), 79 (100).
(E/Z)-2-(2,4-Dibenzyloxyphenyl)-5-(propenyl)benzofuran (2a);
Typical Procedure
Bromobenzofuran 4a (6.1g, 12.5 mmol) was dissolved in DME
(100 mL), and Pd(PPh3)4 (0.125 g, 0.625 mmol) was added. The
mixture was stirred at r.t. under N2 for 20 min. Anhyd K2CO3 (1.7
g, 12.5 mmol), H2O (20 mL), and 3a (3.5 g, 12.5 mmol) were added,
and the mixture was heated under reflux under N2 for 30 h. The mix-
ture was cooled to r.t. and extracted with Et2O (3 × 30 mL). The
combined organic layers were dried (Na2SO4) and concentrated.
The crude material was purified by flash chromatography over sili-
ca gel (PE–EtOAc, 5:1) to give the title product 2a as a white solid;
mp 163–165 °C.
MS (EI): m/z (%) = 380 (40, [81Br, M+]), 287 (35), 179 (45), 91
(100).
Anal. Calcd for C21H15BrO2: C, 66.51; H, 3.99. Found: C, 66.27; H,
3.98.
2-(4-Benzyloxyphenyl)-5-bromo-7-methoxybenzofuran (4d)
White solid; mp 146–148 °C.
IR (KBr): 1612, 1506, 1471, 1250 cm–1.
IR (KBr): 1602, 1494, 1453, 1377 cm–1.
1H NMR (400 MHz, CDCl3): d = 7.91–7.93 (m, 1 H), 7.43 (d,
J = 7.2 Hz, 2 H), 7.26–7.44 (m, 10 H), 7.05–7.19 (m, 2 H), 6.63–
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Synthesis of Natural Benzofuran Neolignans
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6.65 (m, 2 H), 6.38–6.46 (m, 1 H), 5.64–6.14 (m, 1 H), 5.14 (s, 2 H),
5.03 (s, 2 H), 1.84–1.86 (m, 3 H).
13C NMR (100 MHz, CDCl3): d = 158.9, 155.8, 151.7, 151.5, 135.7,
135.5, 131.2, 130.3, 129.2, 128.9, 127.71, 127.65, 127.2, 127.1,
127.0, 126.67, 126.63, 126.55, 119.8, 116.9, 112.3, 109.4, 109.1,
105.3, 103.6, 99.9, 69.6, 69.3, 17.43, 13.6.
1H NMR (400 MHz, CDCl3): d = 7.29–7.47 (m, 7 H), 7.09–7.17 (m,
1 H), 6.94 (d, J = 8.3 Hz, 1 H), 6.72–6.89 (m, 2 H), 6.51 (dd,
J = 11.5, 1.3 Hz, 1 H), 5.76–5.81 (m, 1 H), 5.21 (s, 2 H), 4.04 (s, 3
H), 3.99 (s, 3 H), 1.94–1.96 (m, 3 H).
13C NMR (100 MHz, CDCl3): d = 156.4, 149.8, 148.7, 144.5, 142.7,
136.9, 133.4, 132.3, 130.9, 130.2, 128.6, 128.0, 127.9, 127.3, 126.0,
123.9, 118.2, 118.0, 115.9, 115.7, 114.0, 113.3, 113.1, 109.9, 108.7,
107.8, 100.6, 99.8, 71.0, 56.2, 56.1, 14.7.
MS (EI): m/z (%) = 446 (10, [M+]), 355 (7), 91 (100).
Anal. Calcd for C31H26O3: C, 83.38; H, 5.87. Found: C, 83.20; H,
6.13.
MS (EI): m/z (%) = 400 (20, [M+]), 369 (100), 225 (40).
Anal. Calcd for C26H24O4: C, 77.98; H, 6.04. Found: C, 78.16; H,
6.28.
(E/Z)-2-(2,4-Dibenzyloxyphenyl)-7-methoxy-5-(propenyl)ben-
zofuran (2b)
White solid; mp 120–122 °C.
IR (KBr): 1611, 1506, 1463, 1287, 1186 cm–1.
(E)-2-(2,4-Dihydroxyphenyl)-5-(propenyl)benzofuran (1a);
Typical Procedure
To a solution of 2a (4.5 g, 10 mmol) in CH2Cl2 (250 mL) was added
TiCl4 (2.4 mL, 22.0 mmol) dropwise by a syringe at r.t. The mixture
was stirred until completion of the reaction (monitored by TLC).
The mixture was quenched by slowly adding distilled H2O (25 mL)
and treated with activated carbon. After filtration of the resulting
mixture and concentration, the residue was subjected to flash chro-
matography over silica gel (PE–EtOAc, 3:1) to give the title product
1a as a white solid; mp 179–181 °C (Lit.7a mp 181–184 °C).
1H NMR (400 MHz, CDCl3): d = 8.05 (dd, J = 9.6, 5.6 Hz, 1 H),
7.35–7.51 (m, 10 H), 7.13 (d, J = 12.4 Hz, 1 H), 7.04 (dd, J = 2.8,
1.0 Hz, 1 H), 6.69–6.80 (m, 3 H), 6.43–6.52 (m, 1 H), 5.74–6.21 (m,
1 H), 5.21 (s, 2 H), 5.10 (s, 2 H), 4.05 (s, 3 H), 1.89–2.06 (m, 3 H).
13C NMR (100 MHz, CDCl3): d = 152.8, 144.8, 144.4, 142.3, 141.7,
136.7, 136.5, 133.8, 133.1, 131.8, 131.6, 131.5, 130.4, 128.7, 128.6,
128.3, 128.2, 128.15, 128.10, 127.7, 127.6, 127.57, 125.6, 124.2,
113.6, 113.2, 107.9, 106.3, 104.9, 104.89, 104.4, 100.8, 100.79,
70.6, 70.3, 56.2, 56.15, 18.37, 14.65.
IR (KBr): 3435, 2924, 2854, 1622, 1453 cm–1.
1H NMR (400 MHz, CDCl3): d = 7.89–7.93 (m, 1 H), 7.42 (d,
J = 7.2 Hz, 2 H), 7.05–7.19 (m, 2 H), 6.62–6.64 (m, 2 H), 6.45 (d,
J = 17.1 Hz, 1 H), 6.07–6.14 (m, 1 H), 4.64 (s, 2 H), 4.19 (s, 1 H),
1.84 (d, J = 6.2 Hz, 3 H).
MS (EI): m/z (%) = 476 (15, [M+]), 386 (20), 91 (100).
Anal. Calcd for C31H26O3: C, 83.38; H, 5.87. Found: C, 83.20; H.
5.59.
(E)-2-(2,4-Dihydroxyphenyl)-7-methoxy-5-(propenyl)benzofu-
ran (1b)
(E/Z)-2-(4-Benzyloxyphenyl)-5-(propenyl)benzofuran (2c)
White solid; mp 195–197 °C.
IR (KBr): 1611, 1505, 1253, 1026 cm–1.
1H NMR (400 MHz, CDCl3): d = 7.72–7.80 (m, 2 H), 7.34–7.47 (m,
8 H), 7.05 (dd, J = 9.2, 2.8 Hz, 2 H), 6.86 (d, J = 11 Hz, 1 H), 6.17–
6.55 (m, 1 H), 5.73–5.85 (m, 1 H), 5.13 (s, 2 H), 1.89–1.95 (m, 3 H).
13C NMR (100 MHz, CDCl3): d = 159.2, 156.4, 154.0, 136.7, 132.5,
131.1, 129.7, 128.6, 128.1, 127.48, 127.45, 126.4, 125.1, 124.4,
122.0, 117.7, 115.2, 110.8, 99.8, 70.1, 18.5.
White solid; mp 169–171 °C (Lit.7a mp 172–174 °C).
IR (KBr): 3390, 2927, 1621, 1453 cm–1.
1H NMR (400 MHz, CDCl3): d = 8.04–8.07 (m, 1 H), 7.04–7.15 (m,
2 H), 6.69–6.80 (m, 3 H), 6.49 (d, J = 16.2 Hz, 1 H), 6.14–6.23 (m,
1 H), 4.75 (s, 1 H), 4.45 (s, 1 H), 4.05 (s, 3 H), 1.91 (d, J = 5.4 Hz,
3 H).
(E)-2-(4-Hydroxyphenyl)-5-(propenyl)benzofuran (1c)
MS (EI): m/z (%) = 340 (50, [M+]), 249 (75), 91 (100).
White solid; mp 196–198 °C (Lit.7a mp 208–211 °C).
IR (KBr): 3298, 1604, 1508, 1456 cm–1.
Anal. Calcd for C24H20O2: C, 84.68; H, 5.92. Found: C, 84.39; H,
5.63.
1H NMR (400 MHz, CDCl3): d = 7.77–7.80 (m, 2 H), 7.49–7.50 (m,
1 H), 7.04–7.06 (m, 2 H), 6.84–6.87 (m, 3 H), 6.49 (d, J = 17.3 Hz,
1 H), 6.18–6.24 (m, 1 H), 4.86 (s, 1 H), 1.90 (d, J = 5.2 Hz, 3 H).
(E/Z)-2-(4-Benzyloxyphenyl)-7-methoxy-5-(propenyl)benzofu-
ran (2d)
White solid; mp 158–160 °C.
IR (KBr): 1608, 1505, 1383, 1248 cm–1.
(E)-2-(4-Hydroxyphenyl)-7-methoxy-5-(propenyl)benzofuran
(1d)
White solid; mp 176–178 °C (Lit.7a mp 177–179 °C).
1H NMR (400 MHz, CDCl3): d = 7.74 (d, J = 8.8 Hz, 2 H), 7.25–
7.39 (m, 5 H), 6.95–7.02 (m, 3 H), 6.74–6.78 (m, 1 H), 6.65 (s, 1 H),
6.37–6.45 (m, 1 H), 5.67–6.21 (m, 1 H), 5.04 (s, 2 H), 3.97 (s, 3 H),
1.82–1.89 (m, 3 H).
13C NMR (100 MHz, CDCl3): d = 158.2, 155.5, 144.0, 143.6, 141.8,
135.8, 133.1, 132.4, 130.4, 130.3, 130.0, 129.3, 127.6, 127.0, 126.5,
125.5, 124.9, 123.5, 122.5, 114.2, 112.3, 109.7, 107.0, 103.5, 99.2,
69.1, 55.19, 55.15.
IR (KBr): 3338, 1667, 1458, 1377 cm–1.
1H NMR (400 MHz, CDCl3): d = 7.72–7.75 (m, 2 H), 6.96–7.02 (m,
3 H), 6.74–6.78 (m, 1 H), 6.65 (s, 1 H), 6.44 (d, J = 16.1 Hz, 1 H),
6.10–6.15 (m, 1 H), 4.65 (s, 1 H), 3.97 (s, 3 H), 1.86 (d, J = 5.4 Hz,
3 H).
(E)-2-(4-Hydroxy-3-methoxyphenyl)-7-methoxy-5-(prop-
enyl)benzofuran (1e)18
White solid; mp 198–199.5 °C.
IR (KBr): 3419, 2931, 1605, 1583, 1477, 1437, 1142 cm–1.
1H NMR (400 MHz, CDCl3): d = 7.46 (d, J = 7.2 Hz, 2 H), 7.09–
7.16 (m, 1 H), 6.72–6.97 (m, 3 H), 6.49–6.52 (d, J = 16.8 Hz, 1 H),
5.98–6.10 (m, 1 H), 5.79 (s, 1 H), 4.05 (s, 3 H), 3.96 (s, 3 H), 1.95
(d, J = 5.5 Hz, 3 H).
MS (EI): m/z (%) = 370 (55, [M+]), 279 (100), 165 (30), 91 (80).
Anal. Calcd for C25H22O3: C, 81.06; H, 5.99. Found: C, 81.29; H,
5.72.
(E/Z)-2-(4-Benzyloxy-3-methoxyphenyl)-7-methoxy-5-(prop-
enyl)benzofuran (2e)
White solid; mp 104–105.4 °C.
IR (KBr): 1609, 1513, 1275 cm–1.
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PAPER
2-(4-Hydroxy-3-methoxyphenyl)-7-methoxy-5-propylbenzofu-
ran (1f)
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mp 105–107 °C; (Lit.16 mp 106–107 °C).
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1H NMR (400 MHz, CDCl3): d = 7.19 (s, 1 H), 6.45–6.77 (m, 5 H),
5.47 (s, 1 H), 3.80 (s, 3 H), 3.78 (s, 3 H), 2.40 (t, J = 7.4 Hz, 2 H),
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Acknowledgment
We gratefully acknowledge the National Nature Science Founda-
tion of China (Grant 20672014) for financial support and Dr. Yao
Ma for revising this manuscript.
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Synthesis 2010, No. 15, 2547–2552 © Thieme Stuttgart · New York